(FDA placed a clinical hold on the Pediatric Program requiring retigabine discontinuation in subjects; early termination allows for timely reporting of results.)

Sponsor:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT01668654

First Posted: August 20, 2012

Last Update Posted: January 9, 2017

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
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The purpose of this study is to evaluate the long-term safety and tolerability of retigabine/ezogabine as an adjunctive treatment in subjects with either partial onset seizures (12 to < 18 years old) or Lennox-Gastaut Syndrome (12 to <30 years old) who have participated in a previous ("parent") study.

Number of Participants (Par.) With Any Adverse Event (AE) or Serious Adverse Event (SAE) During the Treatment Period [ Time Frame: From the start of study medication until the end of Follow-Up (up to 178 days) ]

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of the study medication, whether or not considered related to the study medication. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment was exercised in deciding whether reporting was appropriate in other situations. Please refer to the AE/SAE module for a list of non-serious AEs and SAE.

Number of Participants With AEs Leading to Withdrawal [ Time Frame: From the start of study medication until the end of the Follow-Up Visit (up to 178 days) ]

An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of the study medication, whether or not considered related to the study medication. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment was exercised in deciding whether reporting was appropriate in other situations. Please refer to the AE/SAE module for a list of non-serious AEs and SAE.

Number of Participants With Vital Signs Outside the Pre-determined Clinically Important Findings or Outside the Normal Ranges at Any Time During the Study [ Time Frame: Eligibility Assessment (Visit 1), Visit 4, Visit 5, Visit 6, Visit 7, Early Withdrawal (EW) Visit, and Follow-Up (FU) Visit (up to 178 days) ]

Vital sign assessment included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate and body temperature measurements. SBP, DBP and heart rate were measured at the following Visits: 1, 4, 5, 6, 7, EW and the FU Visit after the participants were in the seated position for 5 minutes.

Vital sign assessment included SBP and DBP measurements. SBP and DBP were measured at the following Visits: 1, 4, 5, 6, 7, EW, and the FU Visit after the participant was in seated position for 5 minutes. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Vital sign assessment included heart rate measured at the following Visits: 1, 4, 5, 6, 7, EW, and the FU Visit after the participant was in seated position for 5 minutes. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Vital sign assessment included body temperature measurements at the following Visits: 1, 4, 5, 6, 7, EW, and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Body height was measured without shoes and wearing light clothing at the following Visits: 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Body weight was measured without shoes and wearing light clothing at the following Visits: 1, 4, 5, 6, 7, EW and FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

BMI is calculated as weight in kilograms (kg) divided by the square of their height in metres (m^2). BMI was measured at the following Visits: 1, 4, 5, 6, 7, EW and FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

The 12-lead ECG was recorded in a supine position at the Eligibility Assessment Visitand the EW Visit after having kept a participant at rest in this position for 10 minutes. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Number of Participants With Abnormal Clinically Significant ECG Findings Based on Investigator Judgment at Anytime During the Study [ Time Frame: Eligibility Assessment and EW Visit ]

The 12-lead ECG was recorded in a supine position at the Eligibility Assessment Visit andthe EW Visit after having kept a participant at rest in this position for 10 minutes. Abnormal findings were analyzed as clinically significant (CS) and not clinically significant (NCS). The study investigator judged the ECG abnormailities as CS or NCS.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Albumin, total protein, hemoglobin, and mean corpuscle hemoglobin concentration parameters were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Blood Urea Nitrogen (BUN)/Creatinine and Urine Albumin/Creatinine were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Creatinine, direct bilirubin, indirect bilirubin, total bilirubin, uric acid, and urine creatinine concentration parameters were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included measurements of endocrine and urinalysis parameters. TSH and urine albumin parameters were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Basophils, eosinophils, lymphocytes, monocytes, segmented neutrophils, total neutrophils and red cell distribution width (RDW) parameters were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Hematocrit was measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Mean corpuscle volume and mean platelet colume parameters were measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. Mean corpuscle hemoglobin was measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical laboratory assessments included hematology, chemistry and urinalysis parameters. The red blood cell count was measured at Visits 1, 4, 5, 6, 7, EW and the FU Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

The PVR urine test measured the amount of urine left in the bladder after urination. The PVR bladder ultrasound was performed by an urologist, a qualified technician or by an appropriately trained qualified study nurse at Visits 1, 6, and the EW Visit. Change from Baseline was calculated by subtracting the Baseline value from the individual post-dose values. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Changes From Baseline in Cognition as Measured by the Leiter-R at the Indicated Time Points [ Time Frame: Baseline, Eligibility Assessment (Visit 1) up to 178 days ]

he Leiter International Performance Scale or simply Leiter is an intelligence test for children and adolescents, with norms ranging from 2 to 20 years. For all ages, it yields an intelligence quotient (IQ) and a measure of logical ability. It is comprised of ten subtests, seven of which were relevant to the 12-18 years age group. The administration time was approximately 40 minutes. During the study, only the parent/caregiver completed this questionnaire while the participants were within the age range (i.e. <20 years). Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). The parent study did not measure baseline cognition, behavior, and learning so changes from baseline were not available for participants in this study.

Changes From Baseline in Behaviour as Measured by the Child Behavior Checklist (CBCL) at the Indicated Time Points [ Time Frame: Baseline, Eligibility Assessment (Visit 1) up to 178 days ]

The CBCL is a widely used parent report questionnaire identifying behavioural and emotional problems in children. The checklist is comprised of a number of statements about the child's behavior, e.g. acts too young for his/her age. Responses were recorded on a likert scale: 0 = not true, 1 = somewhat or sometimes true, 2 = very true or often true. The preschool checklist contained 100 questions and the school-age checklist contained 120 questions. During the study, only the parent/caregiver completed this questionnaire while the participants were within the age range (i.e. <18 years). Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). The parent study did not measure baseline cognition, behavior, and learning so changes from baseline were not available for participants in this study.

Changes From Baseline in Learning as Measured by the Wide Range Assessment of Memory and Learning , 2nd Edition (WRAML2) at the Indicated Time Points [ Time Frame: Baseline, Eligibility Assessment (Visit 1) up to 178 days ]

The WRAML2 is a standardized test that measures an individual's memory functioning. It evaluates both visual and verbal, immediate and delayed memory ability along with the acquisition of new learning. The WRAML2 core battery is composed of two verbal, two visual, and two attention concentration subtests, yielding a verbal memory index, a visual memory index and an attention-concentration index. Together, these tests yield the general memory index. The administration time is approximately 40 minutes. During the study, this test was administered if the participant was within the age range (i.e. >9 years). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). The parent study did not measure Baseline cognition, behavior, and learning so changes from Baseline were not available for participants in this study.

Number of Participants With Sexual Maturation Based on the Tanner Stage I to Stage V of Puberty in Participants <=18 Years Old Throughout the Study [ Time Frame: Eligibility Assessment (Visit 1) and EW Visit ]

The number of participants who advanced a stage between the eligibility visit and the EW Visit was recorded. Tanner stage I is defined as no pubic hair at all (prepubertal Dominic state); stage II is defined as a small amount of long, downy hair with slight pigmentation at the base of the penis and scrotum (males) or on the labia majora (females); stage III is defined as when the hair becomes more coarse and curly, and begins to extend laterally; stage IV is defined as adult-like hair quality, extending across pubis but sparing medial thighs; and stage V is defined as when the: hair extends to medial surface of the thighs. The investigator assessed the participant's sexual development in participants <18 years old based on the Tanner Stages of Puberty.

Number of Days of Exposure to Retigabine/Ezogabine TID by Individual Participant [ Time Frame: Treatment Phase plus Taper Phase (up to 97 days) ]

Total number of days each participant was exposed to Retigabine/Ezogabine are recorded here.

Secondary Outcome Measures:

Percent Change From Baseline in the Seizure Frequency at the Indicated Time Points [ Time Frame: Basline, Eligibility Assessment (Visit 1) up to 178 days ]

The percentage reduction from Baseline in the seizure frequency was summarized using descriptive statistics. The frequencies and percentages were computed for a reduction in seizure frequency of >50% as well as for a 100% reduction (seizure-free). Increases of >50% in seizure frequency was also summarized. The percentage of seizure-free days wasere also analyzed. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Number of Participants Who Were Responders During the Treatment Period [ Time Frame: Eligibility Assessment (Visit 1) up to 178 days ]

A ''responder'' is defined as >50% reduction from Baseline in the seizure frequency. Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

The Clinical Global Impression (CGI) scale provided an overall clinician-determined summary measure. It had 2 components: the CGI-Severity of Illness (CGI-S) scale and the CGI- Improvement (CGI-I) scale which rated the change from Baseline. The CGI-I scale scores range from 0 to 7 and are interpreted as 0=not assessed, 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Clinical Global Impression-Severity of Illness (CGI-S) Assessment at the Indicated Time Points [ Time Frame: Baseline, Eligibility Assessment (Visit 1) up to 178 days ]

The Clinical Global Impression (CGI) scale provided an overall clinician-determined summary measure. It had 2 components: the CGI-Severity of Illness (CGI-S) scale and the CGI-Improvement (CGI-I) scale which rated the change from Baseline. The CGI-S was a 7-point scale that required the investigator to rate the severity of the participant's epilepsy relative to the investigator's past experience with other participants with the same diagnosis. The CGI-S scale scores range from 0 to 7 and are interpreted as 0=not assessed, 1=normal, 2=borderline, 3=mild, 4=moderate, 5=marked, 6=severe, 7=extremely severe. Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Change From Baseline in Child Health Status as Measured by the Child Health Questionnaire (CHQ) in Participants <18 Years Old at the Indicated Time Points [ Time Frame: Baseline, Eligibilty Assessment (Visit 1), EW Visit and FU Visit (up to 178 days) ]

The CHQ comprises scales specifically developed for children and adolescents aged five years and older. The CHQ assesses a child's physical, emotional, and social well-being from the perspective of a parent or guardian. The questionnaire was completed by a parent/caregiver and administration time was approximately 30 minutes. The parent/caregiver completed this questionnaire while the participant was within the age range (i.e. <18 years). Baseline was the first pre-Retigabine assessment conducted in the parent study GSK113284 (NCT014945840). Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Area Under the Plasma Concentration-time Curve (AUC) Following Oral Administration of Retigabine/Ezogabine at the Indicated Time Points [ Time Frame: Eligibility Assessment (Visit 1) up to 178 days ]

AUC is defined as the area under the plasma drug concentration-time curve, reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in milligram*hour per Liter (mg*h/L). Blood samples for population PK analysis of retigabine/ezogabine were taken at clinic visits where routine clinical laboratory samples were also taken. Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled.

Apparent Clearance (CL/F) Following Oral Administration of Retigabine/Ezogabine at Indicated Time Points [ Time Frame: Eligbility Assessment (Visit 1), up to 178 days ]

Blood samples for population pharmacokinetic analysis of retigabine/ezogabine were taken at clinic visits where routine clinical laboratory samples were also taken. CL/F, where CL is the calculated as dose/AUC and F is the oral bioavailability of the drug. Because the study was terminated prematurely and the sample size is small, summary statistics were not compiled

retigabine/ezogabine will be administered three times a day (TID) as add-on therapy based on weight

Drug: retigabine/ezogabine

retigabine/ezogabine will be administered three times a day (TID) as add-on therapy based on weight

Detailed Description:

Epilepsy is among the most common serious neurologic disorders in childhood. Medicines with novel actions of mechanisms of action are needed to try to address the unmet clinical need for seizure control in patients with treatment-resistant epilepsy. The purpose of this study is to evaluate the long-term safety and tolerability of retigabine/ezogabine as an adjunctive treatment in subjects with either partial onset seizures (12 to < 18 years old) or Lennox-Gastaut Syndrome (12 to <30 years old) who have participated in a previous ("parent") study.

Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:

12 Years to 29 Years (Child, Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Has participated in either a Phase II or Phase III retigabine/ezogabine clinical trial evaluating partial onset seizures or seizures comprising Lennox-Gastaut syndrome and met the requirements defined in the parent study to transition into the open-label extension study

Investigator and caregiver consider it beneficial for the patient to continue treatment with retigabine/ezogabine

Female subjects of child-bearing potential (after menarche) must either not be sexually active or must be practicing an acceptable method of contraception (documented in the medical chart) from two weeks prior to administration of study medication and for 28 days after completion or premature discontinuation from the study

Subject is living with his/her custodial parent(s) or legal guardian(s) and has contact with them on a daily basis

Written informed consent is obtained from the subjects parent/guardian and accompanying assent from subject. The subject, and/or his/her custodial parents(s) or legal guardian(s) have the ability to comprehend the key components of the informed consent form

Exclusion Criteria:

Has insufficient ability to articulate the presence or absence of urinary tract symptoms

Has experienced an adverse event, clinically significant laboratory abnormality or was discontinued from the parent study due to a reason that in the investigator's judgment would preclude enrollment to the study

Has any abnormality on 12-lead ECG which is clinically significant in the opinion of the investigator, or has a corrected QT interval (using either Bazett's or Fridericia's) >500msec ( >530 msec for subjects with Bundle Branch Block), uncorrected QT interval >600msec, or change from baseline QTc >60msec

Has a history of one or more renal calculi

Has disturbances of micturition or known urinary obstructions, including renal calculi

Has a documented anatomical stricture or other anatomical abnormality of the urinary tract system that has the potential to interfere with urinary flow

Has experienced 2 or more objectively documented urinary tract infections in the preceding 12 months

Has a history of inadequate fluid intake and clinically significant dehydration in the preceding 6 months

Within the preceding month, has taken anti-cholinergic medication on an ongoing basis

Has active suicidal plan/intent or has had active suicidal thoughts in the past 6 months or has history of suicide attempt in the last 2 years or more than one lifetime suicide attempt

Is planning surgery or implantation of a vagus nerve stimulator to control seizures during the study

Is currently or has been abusing substance(s) or any medications in the 12 months prior to study entry

Has taken an investigational drug (exception retigabine/ezogabine), or used an investigational device, within the previous 30 days prior, or plans to take an investigational drug anytime during the study

Females who are lactating or are pregnant

Unwillingness or inability to follow the procedures outlined in the protocol

The subject is felt, by the investigator, to be unsuitable for inclusion in the study

Children in care

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01668654